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  • Title: [Mutation of human O6-alkylguanine-DNA alkyltransferase confers resistance to O6-benzylguanine].
    Author: Wan Y, Wu D, Gao H.
    Journal: Zhonghua Zhong Liu Za Zhi; 2000 Jul; 22(4):290-3. PubMed ID: 11778552.
    Abstract:
    OBJECTIVE: O6-alkylguanine-DNA alkyltransferase (O6-AGT), capable of repairing DNA damage, is responsible for tumor cell resistance to nitrosourea. While O6-benzylguanine as a selective inhibitor of AGT helps reverse drug resistance, it would aggravate myelo-suppression. This investigation is to generate AGT mutant and see if it would confer resistance to O6-benzylguanine-induced inhibition but leave its alkyltransferase activity intact. METHODS: Human O6-methylguanine-DNA methyltransferase (MGMT) cDNA was mutated by site-directed mutagenesis. The mutant cDNA was transferred into E. coli and the protein expressed was purified. The activity of the mutant MGMT was determined in vitro with O6-(3H)-methylguanine-DNA as substrate. RESULTS: Two mutant MGMT proteins were obtained: G156A and P140A, with glycine-to-alanine mutation at position 156 and proline-to-alanine mutation at position 140, respectively. The AGT activity of both mutants was similar to that of the wild type MGMT. However, their resistance to O6-benzylguanine was significantly increased up to 105.8 and 13.5 fold, respectively as compared to that of the wild type MGMT. CONCLUSION: The results suggested that transduction of the mutant MGMT herein reported into hematopoietic progenitor cells may lead to their selective resistance to the combined use of O6-benzylguanine and alkylating agents designed to overcome tumor resistance to nitrosourea treatment.
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